FIXED DRUD ERUTION

James WD, Berger TG, Elston DM. Andrews Disease Skin of the clinical
dermatology. California: Elsevier, 2011 : 116p

Fixed drug reactions (FDE) are common. Fixed drug eruptions

are so named because they recur at the same site with each
exposure to the medication. The time from ingestion of the
offending agent to the appearance of symptoms is between 30
minutes and 8 hours, averaging 2 hours. In most patients, six
or fewer lesions occur, and frequently only one. Uncommonly,
fixed eruptions may be multifocal with numerous lesions (Fig.
6-23). They may present anywhere on the body, but half occur
on the oral and genital mucosa. Fixed eruptions represent 2%
of all genital ulcers evaluated at clinics for sexually transmitted
diseases, and are not infrequent in young boys. In males
lesions are usually unifocal and can affect the glans or shaft of
the penis. FDE of the vulva is often symmetrical, presenting
as an erosive vulvitis, with lesions on the labia minora and
majora and extending on to the perineum. Other unusual variants
of FDE include eczematous, urticarial, papular, purpuric,
linear, giant, and psoriasiform. At times, some lesions of FDE
will not reactivate with exposure due to a presumed refractory
period which may last from weeks to months.
Clinically, an FDE begins as a red patch that soon evolves
to an iris or target lesion similar to erythema multiforme,
and may eventually blister and erode. Lesions of the genital
and oral mucosa usually present as erosions. Most lesions are
1 to several cm in diameter, but larger plaques may occur,
more of AIDS patients being treated for Pneumocystis jiroveciiresembling
cellulitis. Characteristically, prolonged or permanent
postinflammatory hyperpigmentation results, although a
nonpigmenting variant of an FDE is recognized. With repeated
or continued ingestion of the offending medication, new
lesions may be added, sometimes eventuating in a clinical
picture similar to SJS. Histologically, an interface dermatitis
occurs with subepidermal vesicle formation, necrosis of keratinocytes,
and a mixed superficial and deep infiltrate of neutrophils,
eosinophils, and mononuclear cells. Pigment
incontinence is usually marked, correlating with the pigmentation
resulting from FDEs. As biopsies are generally performed
during the acute stage of a recurrence, the stratum
corneum is normal. Papillary dermal fibrosis and deep perivascular
pigment incontinence are commonly present from prior
episodes. This contrast between a normal stratum corneum
(suggesting an acute process) and chronic dermal changes is
virtually pathognomonic of FDE.
Medications inducing FDEs are usually those taken intermittently.
Many of the NSAIDs, especially pyrazolone derivatives,
paracetamol, naproxen, oxicams, and mefenamic acid,
cause FDE, with a special predilection for the lips. Sulfonamides,
trimethoprim, or the combination are now responsible for the
majority of genital FDEs. Barbiturates, tetracyclines, phenolphthalein
(in laxatives), acetaminophen, cetirizine, celecoxib,
dextromethorphan, hydroxyzine, quinine, lamotrigine, phenylpropanolamine,
erythromycin, and Chinese and Japanese
herbs are other possible causes. The risk of developing an FDE
has been linked to HLA-B22. Patch tests with various concentrations
of the offending medication can reproduce the lesion
on affected but not unaffected skin. Tape-stripping the skin
before applying the suspected medication in various vehicles
may increase the likelihood of a positive patch test. This technique
appears to be most useful in pyrazolonederivativerelated
reactions that are reproduced in 85% or more of cases.
Occasionally, FDEs do not result in long-lasting hyperpigmentation.
The so-called nonpigmenting FDE is distinctive,
and has two variants. One is the pseudo-cellulitis or scarlatiniform
type which is characterized by large, tender, erythematous
plaques that resolve completely within weeks, only to
recur on reingestion of the offending drug (Fig. 6-24).
Pseudoephedrine hydrochloride is by far the most common
culprit. The second variant is the baboon syndrome, also called
symmetrical drug-related intertriginous and flexural exanthema
(SDRIFE). SDRIFE preferentially affects the buttocks,
groin, and axilla with erythematous, fixed plaques.
Histologically, a giant cell lichenoid dermatitis can be seen in
this setting.
The diagnosis of FDE is often straightforward and is elucidated
by the history. However, confirmation with provocation
tests can be performed. Due to the refractory period, provocation
tests need to be delayed at least 2 weeks from the last
eruption. If an oral provocation test is considered, the initial
challenge should be 10% of the standard dose, and patients
with widespread lesions (SJS/TEN-like) should not be challenged.
Patch testing using a drug concentration of 1020% in
petrolatum or water applied to a previously reacted site is
the recommended approach. In most patients the treatment
is simply to stop the medication. Desensitization can be
successful.
Lesions of an FDE contain intraepidermal CD8+ T cells with
the phenotypic markers of effector memory T cells. These
epidermal-resident T cells produce IFN-. Such cells are found
in resolved lesions of HSV, suggesting they are a defense
mechanism preventing viral reactivation in the epidermis.
Once the medication is stopped, the abundant CD4+ Fox P3+
T cells (T-regs) in lesions of FDE are felt to downregulate the
eruption. In SJS/TEN patients, such T-regs are found in much
fewer numbers than in FDE, explaining the progression of
SJS/TEN despite stopping of the medication. Resident mast
cells in lesions of FDE may be the cells initially activated with
drug exposure, explaining the rapid onset of the lesion.
FIXED DRUG ERUPTION
Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology Volume One Third
Edition.Elsevier. USA. 2012 : 369p

In fixed drug eruptions (FDE), the lesions develop 1 to 2 weeks after a

first exposure. With subsequent exposures, they appear within 24
hours. Clinically, one or a few, round, sharply demarcated erythematous
and edematous plaques are seen (Fig. 21.10A), sometimes with a dusky,
violaceous hue, central blister or detached epidermis (Fig. 21.10B,C).
The lesions can be found anywhere on the body, but favor the lips, face,
hands, feet and genitalia. An erosion may develop centrally (Fig.
21.10D,E) and the lesions progressively fade over several days, often
leaving a residual postinflammatory brown pigmentation (Fig. 21.10F).
Upon readministration of the causative drug, the lesions recur at
exactly the same sites. With each recurrence, additional sites of involvement
may appear or the number of lesions may remain constant. Thepresence of
numerous lesions is referred to as generalized FDE, and it
may be difficult to distinguish from erythema multiforme or SJS (when
the oral mucosa is also involved).
A non-pigmenting variant of FDE, with large erythematous edematous
plaques has also been described, occurring primarily after administration
of pseudoephedrine. It has been also observed with other
drugs, e.g. NSAIDs, acetaminophen, tetrahydrozoline (eyedrops).
Linear FDE is a rare variant and could be confused with linear lichen
planus.
Histopathology reveals a superficial and deep interstitial and perivascular
infiltrate within the dermis, composed of lymphocytes, eosinophils
and sometimes neutrophils. There may be necrotic keratinocytes
in the epidermis (Fig. 21.10G). Dermal melanophages are often the
only histologic finding in non-inflammatory lesions.The drugs most frequently
associated with FDE are sulfonamides (in
some series, up to 75% of cases), NSAIDs (in particular, phenazone
derivatives), barbiturates, tetracyclines and carbamazepine40,41.
Phenolphthalein-induced FDE is seen less commonly because it has
been removed from a number of laxative preparations. Sometimes, the
inducing drug can be readministered without exacerbation, and there
may be a refractory period after the occurrence of a fixed eruption.
Provocation via patch testing in a previously involved site may be useful
in determining the responsible drug (as long as not performed during
the refractory period).
When there is a single lesion, the differential diagnosis includes a
spider or arthropod bite reaction, and when there are many lesions,
erythemamultiforme or SJS. On the genitalia, herpes simplex viral
infections are often considered and a periungual lesion can be mistaken
for paronychia.
Fixed drug eruptions
Weller RB, Hunter H, Mann M. Clinical Dermatology Firth Edition. USA: Willer
Blackwell, 2015: 354p

Round, erythematous or purple, and sometimes bullous

plaques recur at the same site each time the drug is
taken (Figure 25.6). Pigmentation persists between acute
episodes. The glans penis seems to be a favoured site.
The causes of fixed drug eruptions in any country follow
the local patterns of drug usage there, but these change
Figure 25.6 Fixed drug eruption an unusually severe bullous
reaction.
as old drugs drop out of use and are replaced by new
ones with an unknown potential for causing this type of
reaction. For example, in the United Kingdom, three of
the four most common causes of fixed drug eruptions
in 1970 (barbiturates, phenolphthalein and oxyphenbutazone)
are no longer common causes. Paracetamol is currently
themostcommonoffender in theUnitedKingdom;
trimethoprim-sulfa leads the list in the United States.
NSAIDs (including aspirin), antibiotics, systemic antifungal
agents and psychotropic drugs lie high on the list of
other possible offenders.